This invention relates generally to magnetic nanoparticle compositions, and more particularly to magnetic nanoparticle compositions useful in self-controlled hyperthermia treatment.
Diseases of the human body such as malignant tumors are generally treated by excision, chemotherapy, radiotherapy or a combination of these approaches. Each approach has limitations affecting it clinical utility. For example, excision may not be appropriate where the disease presents as a diffuse mass or is in a surgically inoperable location. Chemotherapeutic agents are generally non-specific, thus resulting in the death of both normal and diseased cells. Radiotherapy is also nonspecific and results in the death of normal tissues exposed to ionizing radiation. In addition, some diseases such as tumors, particularly the core of a tumor mass, may be relatively resistant to ionizing radiation or chemotherapeutic agents.
Hyperthermia has been proposed as a cancer treatment, and published evidence confirms that hyperthermia is effective in treating diseases like cancerous growths. It is understood that malignant cells are reliably more sensitive to heat than normal cells. The therapeutic benefit of hyperthermia therapy is mediated through two principal mechanisms: (1) a directly tumoricidal effect on tissue by raising temperatures to greater than 42° C., resulting in irreversible damage to cancer cells; and (2) hyperthermia sensitizes cancer cells to the effects of radiation therapy or to certain chemotherapeutic drugs. The lack of any cumulative toxicity associated with hyperthermia therapy, in contrast to radiotherapy or chemotherapy, further suggests the desirability of developing improved systems for hyperthermia therapy. While considerable success has been observed in treating superficial tumors using hyperthermia therapy, there remains a need for a method of selectively targeting and treating diseased tissue in a patient.
A large fraction of a tumor's mass is made of hypoxic (poorly oxygenated) cells. Hypoxic cells are much more resistive to radiation therapy than euoxic (well oxygenated) cells. It has been reported that when heat and a radiosensitizing agent (e.g., misonidazole) are used in combination with each other, they produce synergistic potentiation effects. See Schneiderman, et al., Radiat. Res. 155:529-35 (2001); Billi, et al., Appl. & Environm. Microbiology 66: 1489-92 (2000); and Hofer, “Hyperthermia and Cancer,” 4th Int. Conf. Scientific and Clinical Applications of Magnetic Carriers, Tallahassee-Fla., pp. 78-80 (2002). In Hofer's report, hypoxic cancer cells subjected to the two agents during irradiation showed a response enhanced by a factor of 4.3, which far exceeded the euoxic cells. However, Hofer's whole body heating approach is not optimal for clinical application on human, because whole-body heating limits the heat dose that can be given. It would be more desirable to provide a combination therapy in which only the tumor region is heated, i.e., selective hyperthermia.
Clinical feasibility of treating cancer by hyperthermia alone has been investigated (Jordan, et al., 2nd Int. Conf. Scientific and Clinical Applications of Magnetic Carriers, Cleveland-Ohio, 29 (1998); Hofer et al., Cancer 58: 279-87 (1976)). Limitations of these methods are due either to the invasive thermometry or in their inability to reach optimal temperature for the tumor sites when noninvasive techniques are used, especially in the treatment of deep-seated tumors.
Localized heating utilizing a ferromagnetic alloy as “thermoseeds” has been investigated. These particles will generate heat when subjected to an applied alternating magnetic field (Jordan, et al., 2nd Int. Conf. Scientific and Clinical Applications of Magnetic Carriers, Cleveland-Ohio, 29 (1998)). However, at least two impediments to clinical implementation have been identified: (1) the lack of uniform heat distribution at the tumor site and the resultant creation of spot overheating that leads to necrosis; and (2) the size of these thermoseed particles are on the order of 1 to 5 cm, making them highly non-biocompatible.
The ability to produce magnetic nanoparticles in recent years has enhanced interest in localized heating. In this technique, magnetic particles are confined on site and are heated by an external oscillating electromagnetic field (Lilly et al., Radiology, 154:243 (1985); Chan, et al., J. Magn. Mater. 122:374 (1993); Jordan, et al., Int. J. Hyperthermia, 12:705 (1996)). Other examples are disclosed in Pankhurst et al., Phys. D: Appl. Phys., 36:R167-81 (2003); Kuznetsov et al., Eur. Cells Mater., 3:75-77 (2003); Jordan et al., J. Magn. Magn. Mater., 201:413-19 (1999). The use of nanomagnetic particles to induce heat at the tumor tissue potentially would minimize side effects by localized heating of only the desired parts of the organism, including tumors located deep inside a patient's body. Unfortunately, conventional magnetic particles make it impossible to control the uneven heating at the tumor site, which may cause local overheating and necrosis of healthy tissue.
It therefore would be desirable to provide improved magnetic particle compositions that reduce or eliminate the problem of uneven heating, and possess a property to self regulate the maximum temperature it can attain making magnetic hyperthermia a more viable therapeutic option.